GABA Receptors in Status Epilepticus

Scientist in lab
Tuesday, February 13, 2018

What is status epilepticus?

  • Status epilepticus (abbreviated to “SE”) is a state of sustained (longer than five minutes), self-sustaining seizures that can be associated with prolonged convulsions or a prolonged alteration in mental state and a distinctive pattern of activity that can be seen on an EEG (electroencephalogram).
  • There is a risk of experiencing death and cognitive and psychological dysfunction as a result SE.
  • SE is associated with rapid changes in the brain.
  • SE can be divided into three stages:
    1. Early SE (characterized by recurrent seizures)
    2. Refractory SE (characterized by seizures that merge)
    3. Late SE (characterized by seizures converting to “recurring discharges”)
  • These stages are usually very close to one another in time.
  • Prompt treatment of SE is critical.
  • SE is treated by benzodiazepines; however, these drugs stop working effectively as seizures progress.

How is status epilepticus studied in the lab?

  • Experimental animals play a critical role in studying SE in the lab. (Learn more about how animals are used for epilepsy research.)
  • Rodents like rats and mice may be given drugs (called “chemoconvulsants”) to simulate SE, allowing scientists to study what happens in the brains of mice with epilepsy versus mice without epilepsy.
  • Depending on the question being studied, scientists may look at the whole animal and its behavior (“in vivo”) or look at a part of its brain (“in vitro,” e.g., neuronal cultures).
  • Scientists using animals for research have a moral, ethical, and scientific obligation to treat them with respect. There are federal organizations (for example, the Institutional Animal Care and Use Committee at the University of Tennessee - Knoxville) in place to verify that experimental animals are not mistreated.

What is the role of GABA receptors in status epilepticus?

  • Gamma amino butyric acid (GABA) is an inhibitory neurotransmitter found in the brain. It dampens down the excitability of neurons.
  • GABA acts through its receptors known as GABA receptors (GABARs).
    • GABARs can be of various types depending on the part of the brain and the function of the brain structure in question.
    • For example, different subtypes of GABARs are important for inhibition of neurons at certain times (“phasic inhibition”) versus sustained times (“tonic inhibition”).
    • GABARs are made up of subunits that are arranged in numerous ways.
  • Studies have shown during SE arising from the hippocampus, GABARs are less effective at inhibiting (dampening) neurons. (The hippocampus is the part of the brain involved with memory, and it is important for generating and sustaining certain kinds of seizures.)
    • Usually, GABARs are present on the synapse (the area of space between two neurons where neurotransmission takes place).
    • However, studies have shown that in SE, GABARs internalize, meaning they are taken up inside the neuron, and cannot do their job of inhibiting neurons as well.
  • Even if GABARs do not get internalized, they can undergo a process called “dephosphorylation” in SE, which may also cause them to do less.
  • Benzodiazepines, such as diazepam, act on GABARs that have the γ2 subunit.
    • These particular receptors get internalized as a result of prolonged seizures.
    • This may explain why benzodiazepines do not act as well in controlling SE as seizures progress.
  • Most of this research comes from animal studies. However, more research, which is underway now, will be important to discover new and better drugs for SE.

Further Reading and Sources

Authored by: Sloka Iyengar PhD | Basic Science Editor on 2/2018

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